Slug is a member of the Slug/Snail superfamily of evolutionarily conserved zinc finger transcriptional repressors. Slug was identified as a functional target of the E2A-HLF fusion oncoprotein in pro-B-cell acute leukemias, in which the E2A-HLF fusion gene was generated by the t(17:19)(q22;p13) chromosomal translocation. Slug is an orthologue of CES-1, which lies downstream of the CES-2 cell-death specification protein of Caenorhabditis elegans, leading our laboratory to a model of leukemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell death pathway. Thus, our laboratory has generated Slug -/- mice and showed that they were more radiosensitive than wild-type mice, dying earlier and at an increased rate after total-body-gamma-irradiation. The irradiated Slug -/- mice have increased apoptosis in hematopoietic stem cells and progenitors compared to irradiated wild-type control mice. My preliminary results further showed that Slug is expressed in subsets of hematopoietic stem and progenitor cells and that its expression is induced 10-fold in a p53-dependent manner in normal bone marrow cells within 2 hours after irradiation. Taken together, these findings indicate that Slug plays an important antiapoptotic role in hematopoietic progenitor cells that have been exposed to gamma-radiation-induced genotoxic stress. The discovery that Slug plays an antiapoptotic role in hematopoietic progenitors raises two key mechanistic questions that will be addressed in two individual specific aims: i) What are the signal transduction pathways downstream of gamma-irradiation-induced DNA damage that upregulate Slug expression? ii) What are the direct downstream targets of Slug in hematopoietic progenitors and what are the signal transduction pathways through which Slug attenuates the apoptotic machinery? The working hypothesis is that Slug negatively regulates p53-mediated apoptotic signaling pathways at a point downstream of p53 activation, leading to attenuation of gamma-radiation-induced apoptosis.